In recent years, in the field of regeneration medicine, with the advent of technology of induced pluripotent stem cells (hereinafter, also abbreviated as “iPS cells”), clinical studies toward practical use of iPS cells are rapidly progressing. For example, clinical tests to age-related macular degeneration patients are already carried out using retinal pigment epithelium cells induced from human iPS cells. In addition, clinical tests using nerve cells, chondrocytes, and the like, derived from human iPS cells are planned to be carried out (see, Non-Patent Literature 1).
The iPS cells are one type of pluripotent stem cells. The pluripotent stem cells include embryonic stem cells (hereinafter, also abbreviated as ES cells), and Epiblast Stem cells, in addition to the iPS cells. In recent years, these pluripotent stem cells have been known to have different basic characteristics depending on differences in animal species from which cells are derived or types of pluripotent stem cells. Specifically, mouse ES cells and mouse iPS cells are close to the early stage of development, can be easily cultured or genetically engineered, and highly proliferate, thus enabling differentiation to be induced efficiently. Such cells are called naïve cells. On the other hand, human ES cells, human iPS cells, and the like, represent epiblast characteristics in a highly-developed stage. Therefore, it is difficult to genetically engineer the cells, and differentiation is biased toward any one specific germ-layer among three germ-layers. Such cells are called primed cells (see, Non-Patent Literature 2). Therefore, in regeneration medicine etc., in order to practically use pluripotent stem cells, a producing method capable of reliably obtaining pluripotent stem cells having characteristics of the naïve state rather than characteristics of the primed state has been demanded.
As a method for producing human iPS cells, a method of introducing so-called Yamanaka four factors (Oct3/4 gene, Sox2 gene, Klf4 gene, and c-Myc gene) into somatic cells (see, Patent Literature 1) has been known. However, the method had a problem that only primed human iPS cells were able to be produced. To date, in order to produce naïve human iPS cells, techniques to induce iPS cells derived from various animals to a naïve state have been developed. Attempt to further introduce other genes into the above-mentioned Yamanaka four factors, and consideration of medium conditions by adding various compounds, have been carried out. For example, in a method of introducing two factors, Nanog and Klf2, and adding LIF (Leukemia inhibitory factor), PD0325901 (MEK inhibitor), CHIR99021 (GSK3 inhibitor) and Go6983 (PKC inhibitor) into a medium (see Non-Patent Literature 3), expression of KLF4 and TFCP2L1 which are known to be naïve gene markers is increased, and, therefore, obtaining of human iPS cells in a state close to the naïve state is reported.
However, the above-mentioned technology has a problem that expression of ESRRB (Estrogen-related receptor beta) that is considered to be a gene important for maintaining of a naïve undifferentiated state is hardly observed (see Non-Patent Literatures 3 and 4), and the like.